Blood tests for the presence of HCV

• ELISA (Enzyme Linked Immunosorbent Assay). The ELISA test for hepatitis C searches the blood sample for certain biochemical sequences that correspond with the presence of antibodies to HCV. Antibodies do not show viral presence only a past exposure to HCV. There are a fair amount of false positives and negatives with this test and antibodies usually are not formed for six months from the time of exposure. This test is inexpensive and is used as the initial screening for HCV. This test is continually being improved.
• RIBA (Recombinant Immunoblot Assay). The RIBA test was developed for use in hepatitis C because of the unreliability of ELISA. This test searches for two different sets of patterns that correspond to HCV antibodies and a test for the presence of a controlled substance. Pathologists have to visually assess the positivity of the result by comparison to controls. The test is highly accurate but not 100%. It is more expensive than an ELISA; therefore it is used as a confirmation tool. This test is continually being improved.
• HCV-RNA BY PCR (Polymerase Chain Reaction). It is the most sensitive test available. This test assesses the presence or absence of the hepatitis C virus itself in the blood, and other body tissue. It can detect minute traces of the HCV in any given medium. It works by taking a sample of the blood and amplifying the nucleic acid associated with the virus many times.

This test does not rely on the forming of antibodies and may be able to detect the virus after only three days of infection.

Being PCR negative does not necessarily mean that HCV has disappeared completely; it may still be at undetectable levels in the blood, and it may still be present in liver cells and in certain white blood cells.

Although PCR has these limitations it is probably the most useful single test that can be used to assess HCV.

• B-DNA for HCV. B-DNA tests for the presence of the virus in the blood, but is less sensitive than the PCR test. It generates an estimate of viral loads above a certain level. PCR can detect as few or less than 1000 genomes, while b-DNA only picks up levels over 350,000. It is often used as a quick test to assess infectivity and viral load. A negative b-DNA test does not mean that you don't have HCV in your blood. Results of these tests may have caused some confusion in some patients. You can be b-DNA negative and PCR positive.
• Genotype Tests assess which specific genotype of Hepatitis C virus is present. HCV is actually a remarkably heterogeneous family of viruses, with at least six distinct genotypes and numerous subtypes. In this country, most patients (approximately 70%) are infected with type 1, which is unfortunately less responsive to treatment than other genotypes. The usefulness of the test is related to the bearing of genotype on prognosis and responsiveness to treatment.

Disease severity

Once the diagnosis is made, the severity of liver disease should be evaluated. The commonly used tools are the ALT levels, liver function tests, abdominal ultrasound and histologic examination of samples obtained in a liver biopsy. The ALT is not a measure of how well the liver is functioning, but more a marker for the presence of inflammation. It correlates poorly with the degree of liver injury and cannot be used as gauge for the progression of disease.

Liver Function Tests

Most liver function tests have a low level of sensitivity for the detection of mild to moderate liver disease. The prothrombin time, serum billirubin and albumin lack specificity and typically become abnormal only after irreversible liver damage has occurred.

Ultrasound

Examination of the liver by ultrasound is useful for detecting other liver diseases, but is not helpful in establishing the severity of ongoing infection or for assessing liver function. Ultrasound can't reliably differentiate a normal liver from one with chronic hepatitis, fibrosis or early cirrhosis. It is, however, useful as a screen for hepatoma, and can often detect ascites (the accumulation of fluid within the abdomen) or possibly collateral venous circulation suggesting portal hypertension.

Liver Biopsy

The only accurate clinical method of determining the severity of liver disease is examination of tissue obtained on a liver biopsy. The assessment of the degree of inflammation and fibrosis present is important in establishing prognosis. A biopsy is not necessary to confirm the diagnosis of Hepatitis C, but it can be a great help to both physicians and patients in making treatment decisions. More detailed information on liver biopsies is provided below.

Treatment

Once the diagnosis of HCV is confirmed, the difficult decision regarding treatment has to be made. The only therapy with proven efficacy is interferon, alone or in combination with Ribavirin. Interferon is a naturally occurring protein used to stimulate the immune system to fight hepatitis and certain forms of cancer. When used to fight hepatitis C, individual responses to treatment may be divided into three broad categories: (1) sustained responders who rid the virus from their blood and have their serum liver enzymes return to normal even six months after therapy is stopped; (2) nonresponders, who do not show a disappearance of viral RNA levels from the blood and do not have their serum liver enzymes return to normal; (3) partial responders, who drop their viral levels and liver enzymes on treatment but fail to maintain these successes once treatment is discontinued.

Commercially, interferon comes as three products, all made using recombinant DNA technology, thus eliminating the risk of transmitting infection. In general, when using interferon alone at the standard dose, there is little difference among the products in terms of their expected side effects as well as response rates. Treatment usually begins with three million units, given three times a week by subcutaneous injection and continues for at least one year. With this regimen, approximately 30% to 40% of patients will normalize their ALT and have no evidence of virus at the end of one year. Unfortunately, six months later, most of those responding will show evidence of recurrence of the virus. Long term, permanent remission is likely to occur in only 10%-15% of patients. Re-treating patients with the same dose of interferon alone does not appear to improve the sustained response rate.

Interferon and Ribavirin

Recently, the combination of interferon and Ribavirin, another anti viral drug, has been approved for treatment. As initial treatment, combination therapy results in a sustained response in about 30% of patients with genotype 1, and 65% of patients with other genotypes. Similar results were attained in relapsed patients retreated with combination therapy for six months.

Side effects

Almost all patients who receive interferon will experience some side effects. These are usually mild and should not require adjustment or discontinuation of therapy. On average, more than 90% of patients complete the therapy. The most frequent complaint is of a "flu-like" syndrome with fatigue, muscle ache and low-grade fever. About 10% or more will also experience mild GI symptoms, some hair loss and depression. When Ribavirin is included in the regimen, hemolytic anemia (blood anemia) and the risk of teratogenicity (fetal abnormalities) also have to be considered.

What to expect from treatment

The goal of therapy to date has been the permanent eradication of the HCV from the liver. Until recently, it hasn't been clear if the absence of virus at six months would imply a long-term response. Additionally, the effect of viral clearance on the progression of liver injury has been unknown. Some of these answers are becoming available from long-term studies:

• If the HCV is absent from the serum six months following therapy, it is very likely that it will remain absent in the long run.
• Liver histology improves in virtually all patients that clear the virus permanently.
• In patients with established cirrhosis that clear the HCV, the risk of progressing to liver cancer appears to be significantly reduced.

The search for improved therapies for HCV continues. To date, antioxidants, including vitamin E, and milk thistle have been shown in small studies to reduce ALT levels in some patients, but do not appear to have any antiviral or histologic effect. No other conventional drug or herbal remedy has been proven in treating HCV.

Therapies that may be available in the near future include:

1. Interferon conjugated with polyethylene glycol. This allows for once a week dosing and more sustained blood levels of interferon.
2. High-dose interferon.
3. Induction therapy of interferon.
4. Maintenance therapy with interferon.
5. Protease/helicase inhibitors.

Conclusion

HVC is the most common cause of chronic viral hepatitis in the United States, currently affecting four million Americans. Left untreated, it may progress to cirrhosis, which in turn can lead to liver failure and hepatocellular carcinoma (liver cancer). The course of chronic HCV is accelerated by alcohol intake and can become worse if complicated by infection with Hepatitis A. Although they can have significant side effects, current treatment regimens with interferon are completed by 90% of those participating and can result in long term-sustained response.